One of the main routes of exposure to Micro- and Nanoplastics (MNPs) is through inhalation, and studies have already reported that they can cause occupational diseases. Therefore, it is of utmost importance to test the effects of MNPs on lung models. However, since the lung is a complex environment, short-term cytotoxicity tests performed on cells grown under standard submerged settings might not be indicative of real-life hazards. For this reason, we tested the impact of different culture systems (submerged (Sub) and air-liquid interface (ALI)) on the polarisation of A549 cells towards an alveolar type II (ATII)-like phenotype to determine the best, and more realistic setup to perform our future experiments with MNPs.